Аннотация
In the search for more selective A2-receptor agonists and on the basis
that appropriate substitution at C2 is known to impart selectivity
for A2 receptors, 2-alkynyladenosines 2a-d were resynthesized and
evaluated in radioligand binding, adenylate cyclase, and platelet
aggregation studies. Binding of 3HNECA to A2 receptors of rat striatal
membranes was inhibited by compounds 2a-d with Ki values ranging
from 2.8 to 16.4 nM. 2-Alkynyladenosines also exhibited high-affinity
binding at solubilized A2 receptors from human platelet membranes.
Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand
3HDPCPX and for the agonist 3HCCPA gave Ki values in the nanomolar
range, and the compounds showed moderate A2 selectivity. In order
to improve this selectivity, the corresponding 2-alkynyl derivatives
of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested.
As expected, the 5'-N-ethyluronamide derivatives retained the A2
affinity whereas the A1 affinity was attenuated, resulting in an
up to 10-fold increase in A2 selectivity. A similar pattern was observed
in adenylate cyclase assays and in platelet aggregation studies.
A 30- to 45-fold selectivity for platelet A2 receptors compared to
A1 receptors was found for compounds 8a-c in adenylate cyclase studies.
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